Muscle loss and fat gain contribute to the disability, pain, and morbidity associated with knee osteoarthritis (OA), and thigh muscle weakness is an independent and modifiable risk factor for it. Published treatment guidelines recommend muscle strengthening to combat sarcopenia and improve muscle quality in knee OA patients;however, previous strength-training studies either used intensities below recommended levels or were generally short (6 to 24 weeks). Consequently, they had low-to-modest effect sizes, could not detect changes in disease progression, did not address underlying OA mechanisms, and provided little lasting clinical benefit. The efficacy of high intensity strength training in improving symptoms, slowing progression, and affecting the underlying mechanisms has not been examined due to the unsubstantiated belief that it might exacerbate symptoms. Our preliminary data show excellent tolerance for high-intensity strength training as well as reduced pain and increased function among older adults with knee OA. Similar studies in healthy older adults found improvements in thigh muscle mass and decreases in thigh fat mass with minimal alteration in total body weight after 16-18 weeks of training. We propose an 18-month, high-intensity strength-training intervention for older adults with knee OA, focused on improving thigh composition. We hypothesize that in addition to short- term clinical benefits, combining greater duration with high intensity will alter thigh composition sufficiently to attain long-term changes in knee-joint forces, decrease inflammation, lower pain levels, and slow progression. Participants (age e 55 yrs;BMI e 25 kg/m2 and d 40 kg/m2) will be randomized to one of 3 groups: high- intensity strength training (75-90% 1RM);low-intensity strength training (30-40%1RM);or attention control. The study sample will consist of 372 ambulatory, community-dwelling persons with: (1) mild-to-moderate medial tibiofemoral OA (KL = 2-3);(2) knee varus malalignment (varus angle e 2 degrees and d 10 degrees);and (3) no participation in a formal strength-training program for more than 30 minutes per week within the past 6 months. The primary clinical aim is to compare the interventions'effects on knee pain, and the primary mechanistic aim is to compare their effects on knee-joint compressive forces during walking, a mechanism that affects the OA disease pathway. Secondary aims will compare intervention effects on additional clinical measures of disease severity;disease progression, measured by MRI;thigh muscle and fat volume, measured by CT;components of thigh muscle function, including hip abductor strength and quadriceps strength, power, and proprioception;additional measures of knee-joint loading;and inflammatory and OA biomarkers. This study is innovative in three ways. First, it tests the efficacy of a high-intensity strength training protocol suitable for an older population with knee OA. Second, it considers both clinical and mechanistic outcomes. Third, it combines exercise intensity and duration to identify a nonpharmacologic therapy capable of improving clinical symptoms and slowing disease progression with minimal adverse effects. PUBLIC HEALTH RELEVANCE: Given the prevalence and impact of OA and the widespread availability of this intervention, assessing its efficacy has immediate and vital clinical impact. Results of this trial will provide critically needed guidance for clinicians in a variety of health professions who prescribe and oversee treatment and prevention of OA-related complications.